1118761-75-3Relevant academic research and scientific papers
Second generation analogues of the cancer drug clinical candidate tipifarnib for anti-chagas disease drug discovery
Kraus, James M.,Tatipaka, Hari Babu,McGuffin, Sarah A.,Chennamaneni, Naveen Kumar,Karimi, Mandana,Arif, Jenifer,Verlinde, Christophe L. M. J.,Buckner, Frederick S.,Gelb, Michael H.
experimental part, p. 3887 - 3898 (2010/08/22)
We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14α-demethylase. Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein farnesyltransferase and display increased potency for killing parasites. This was achieved in a structure-guided fashion by changing the substituents attached to the phenyl group at the 4-position of the quinoline ring of tipifarnib and by replacing the amino group by OMe. Several compounds that kill Trypanosoma cruzi at subnanomolar concentrations and are devoid of protein farnesyltransferase inhibition were discovered. The compounds are shown to be advantageous over other lanosterol 14α-demethylase inhibitors in that they show only modest potency for inhibition of human cytochrome P450 (3A4). Since tipifarnib displays high oral bioavailability and acceptable pharmacokinetic properties, the newly discovered tipifarnib analogues are ideal leads for the development of drugs to treat Chagas disease.
Rational modification of a candidate cancer drug for use against chagas disease
Kraus, James M.,Verlinde, Christophe L. M. J.,Karimi, Mandana,Lepesheva, Galina I.,Gelb, Michael H.,Buckner, Frederick S.
body text, p. 1639 - 1647 (2010/01/07)
Chagas disease is one of the major neglected diseases of the world. Existing drug therapies are limited, ineffective, and highly toxic. We describe a novel strategy of drug discovery of adapting an existing clinical compound with excellent pharmaceutical properties to target a pathogenic organism. The protein farnesyltransferase (PFT) inhibitor tipifarnib, now in phase III anticancer clinical trials, was previously found to kill Trypanosoma cruzi by blocking sterol 14a-demethylase (14DM). We rationally developed tipifarnib analogues that display reduced affinity for human PFT to reduce toxicity while increasing affinity for parasite 14DM. The lead compound has picomolar activity against cultured T. cruzi and is efficacious in a mouse model of acute Chagas disease.
